Bacterial vaginosis (hereafter “By”) is reported to be the most common cause of vaginitis found in women of reproductive age, causing 40-50% of all vaginal infections (Sobel, 1997, “Review Article: Vaginitis,” New Engl J Med 337:1896-1903). BV can cause bothersome symptoms, and can at times increase the risk of acquiring sexually transmitted diseases, such as HIV. BV is thought to represent a synergistic polymicrobial bacterial infection characterized by an overgrowth (lOO×-lOOO×) of bacterial species often found as part of normal vaginal micro flora, including Gardnerella vaginalis, Bacteroides spp. (some now classified as Prevotella spp.), anaerobic Gram-positive cocci, Mobiluncus spp. and Mycoplasma hominis. Accompanying this increase is a marked decrease in Lactobacillus species normally present that are believed to regulate the growth of other vaginal flora. Moreover, hydrogen peroxide-producing strains of Lactobacillus that dominate the vaginal flora of healthy women are replaced by non-hydrogen peroxide-producing strains in women with BV (Amsel et al., 1983, Am J. Med 74:14; Sobel el al, 1990, Infect Med May:24). Generally, studies show that there are greater quantitative than qualitative differences in the vaginal micro flora of women with BV as compared to healthy women, indicating that some of the clinical signs and symptoms of BV may be related to quantitative differences in one or more naturally present microbial species (Masfari et al., 1986, Genitourin Med 62:256). The factors responsible for the initial disruption of, and eventual change in, the balance of species in the vaginal ecosystem are not well understood, and the exact locus of the infection is unknown, complicating efforts for developing suitable treatments.
Metronidazole, approved by the FDA on Jul. 18, 1963, and clindamycin are two of the oldest and most commonly used antibiotics that are prescribed to treat women who suffer from and/or are diagnosed with BV ((CDC 2006 STD Treatment Guidelines MMWR 2006; 55 (No. RR-7)).
Metronidazole is available from numerous sources as oral tablets and capsules, injectable solutions, 0.75 wt % topical lotions, creams and gels, 1.0 wt % topical gels and 0.75 wt % vaginal gels. The topical creams, lotions and gels are generally indicated for the treatment or rosacea, wherein the vaginal gels, for example the 0.75 wt % metronidazole vaginal gel sold by Medicis under the brand name METROGEL VAGINAL®), are indicated for the treatment of BV.
Despite their common use, treatment with the 0.75 wt % vaginal metronidazole gels such as METROGEL VAGINAL®) are less than ideal. To be effective, the gels must be applied once or twice a day for a period of five days.
Moreover, recurrence of BV is commonly observed in up to 30% of women within three months of treatment, whether oral or vaginal. The reasons for recurrence remain unclear. See, e.g., Larsson, 1992, Int J Std Aids 3:239-247; Wilson, 2004, Sex Transm Infect 80:8-11. It has been shown in a double-blind, placebo-controlled crossover trial that intravaginal treatment with a 0.75% metronidazole gel resulted in a recurrence rate of about 15% one month following treatment. See, Hillier et al, June 1993, “Efficacy of Intravaginal 0.75% Metronidazole Gel for the Treatment of Bacterial Vaginosis,” Obstet Gynecol 81(6):963-967. Vulvovaginal candidiasis, commonly known as a yeast infection, is also observed in approximately 10% of women following treatment for BV.
In view of the fact that BV is currently the most prevalent form of vaginal infection in women of reproductive age, there is a real and immediate need for new therapies that address one or more of the shortcomings of currently available BV treatments. For example, it would be desirable to have available an intravaginal treatment that provides an effective cure in a single application, and/or that provides a more effective cure than currently available 0.75 wt % intravaginal metronidazole gels, reduces the rate of recurrence of BV following a successful course of treatment, and/or reduces the incidence of vulvovaginal candidiasis following a successful course of BV treatment.